PROJECT SUMMARY The most significant obstacle in the treatment of neurological disorders is the blood-brain barrier (BBB) which prevents 98% of all potential neuropharmaceuticals from reaching the central nervous system (CNS). Brain derived neurotrophic factor (BDNF) is one of the most intensely studied targets in Parkinson?s disease (PD) as it can reverse disease progression. BDNF AntagoNATs are synthetic oligonucleotide-like compounds capable of upregulating endogenous BDNF expression. AntagoNATs solve the problems of recombinant BDNF therapies including off-target toxicity, immunogenicity, and improper post-translational modification while increasing target specificity, improving neuronal uptake, and providing appropriate subcellular compartmentalization of the expressed protein. Compounds chemically similar to AntagoNATs have been shown to be safe and have been recently FDA approved. Despite the significant promise of BDNF AntagoNAT therapies for PD, they cannot cross the BBB. Current methods to bypass the BBB are expensive, have significant complications, and cannot be easily scaled. The trans-nasal pathway to bypass the BBB holds significant promise however current techniques rely on diffusion through the olfactory mucosa and have major drawbacks including a restricted surface area, variable drug contact, unpredictable pharmacokinetics, limited mucosal residence time, and poor drug stability. This innovative proposal brings together a unique, multi- disciplinary team of experts to overcome each of these challenges. Our group has developed an innovative intranasal heterotopic mucosal grafting technique capable of delivering a wide range of high molecular weight therapeutics directly into the CNS. This method is based on established endoscopic skull base procedures that have been safely performed globally for over a decade. We have previously shown that the BDNF AntagoNAT therapeutic strategy is non-immunogenic, reduces off target toxicity, overcomes the limitations of recombinant neurotrophic protein delivery, and is capable of successfully upregulating BDNF expression in critical end organ targets following transmucosal delivery. We have further demonstrated that the mucosal grafting technique is safe, cost effective, and highly scalable. Finally, our data indicate that our dual-compartment Liposome-in-Gel (LiG) delivery system is capable of protecting oligonucleotide cargo while improving CNS distribution by providing a sustained release depot at the mucosal surface. Our overall goal is to optimize the LiG formulation, create a quantitative pharmacokinetic model of transmucosal BDNF AntagoNAT delivery using LiG, and validate the therapeutic efficacy in two complementary rodent models of PD using histologic, behavioral, and live imaging endpoints. This innovative delivery system for BDNF AntagoNATs represents a platform technology which can eliminate the BBB as a fixed barrier to delivery and enable the use of AntagoNATs in the treatment of multiple currently undruggable CNS disorders. Our proposal is specifically designed to gather the critical pre-clinical data needed to provide a rapid pathway to first-in-human trials.